Multiple Myeloma (MM) is an incurable plasma cell malignancy accounting for 11,000 deaths annually in the US and 20% of deaths from all hematological malignancies. Therefore, there is a great need for the development of therapeutics with efficacy in treating aggressive chemo-resistant MM. Myeloma is characterized by a high degree of genetic heterogeneity, and targeting tumor cell metabolism may provide a unifying therapeutic strategy to target the broader spectrum of cell types. Elevated glucose consumption in MM forms the basis for the diagnostic imaging modality 18fluoro-deoxyglucose positron emission tomography (FOG-PET) in addition to being a prognostic indicator. Glucose metabolism has not however been directly targeted for therapy in any cancer. We recently identified glucose transporters (GLUTs), including GLUT4, as playing a major role in facilitating glucose transport and maintenance of viability in MM. We further demonstrated the utility of repurposing human immunodeficiency virus (HIV) protease inhibitors with off-target inhibitory effects on GLUT4 to target GLUT4 in MM. GLUT4 inhibition leads to growth inhibition and/or apoptosis.
We have recently determined that MM cells that have developed resistance to GLUT4 inhibition/ritonavir utilize mitochondrial metabolism coupled to oxidative phosphorylation (i.e., mitochondrial OXPHOS) in order to remain viable. Metformin HCl, sold under the trademark GLUCOPHAGE®, is a mitochondrial complex 1 inhibitor that can be used to target mitochondrial OXPHOS. GLUT family members exhibit restricted expression profiled in normal tissues and have a rate-limiting role in the glycolytic pathway, suggesting that GLUT inhibition combined with mitochondrial OXPHOS inhibition may provide a cancer therapy having a high therapeutic index. Here, we demonstrate that targeting GLUT4-driven glycolysis with ritonavir and any ensuing compensatory mitochondrial metabolism with metformin elicits potent lethality across a spectrum of cancers. Hence, we propose that HIV protease inhibitors with off-target inhibitory effects on GLUT4 may be repurposed and administered in combination with metformin to treat a spectrum of cancers capable of utilizing glycolytic or mitochondrial metabolism. Ritonavir has also been shown to inhibit other GLUTs. These additional GLUT inhibitory activities may be beneficial to target GLUT-driven malignancies in combination with metformin to target any compensatory mitochondrial metabolism.